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Irinotecan is expected to become a new drug for childhood solid tumors. Sixteen children with relapsed solid tumors received irinotecan 180 mg/m2/day for 3 consecutive days, repeated once after 25 days off. Their original tumors were neuroblastoma in 7, rhabdomyosarcoma in 3, nephroblastoma and undifferentiated sarcoma in 2 each, and primitive neuroectodermal tumor and leiomyosarcoma in 1 each. The average age at trials was 6 years. Partial response was achieved in 5 (31.3%) (neuro-blastoma, rhabdomyosarcoma, nephroblastoma, undifferentiated sarcoma, and leiomyosarcoma), and decrease in tumor marker in the other 2. Irinotecan appears promising, and could become included in the first-line treatment.

A 12-year-old girl presented with a large abdominal tumor. At surgery, a huge pedunculated extraluminal tumor was found arising from the greater curvature of the stomach and invading the surrounding structures, and there were also a submucosal tumor measuring 5 x 4 x 4 cm and multiple intramural nodules beside the main tumor. These lesions, which were removed with 1.0-cm surgical margins, were immunohistochemically positive for c-kit (CD117) and CD34. A diagnosis of gastrointestinal stromal tumor (GIST) was made. The huge size of the tumor (3.6 kg in weight and 36 x 25 x 25 cm in diameter), the invasion of the surrounding structures, and the increased mitotic figures indicated the GIST had malignant potential. Sequence analysis of the polymerase chain reaction product of RNAs from the tumor cells revealed a novel platelet-derived growth factor receptor alpha (PDGFRA) mutation, which would exhibit biologic consequences similar to those of the c-kit mutation. The patient underwent a 3-month course of imatinib mesylate as adjuvant chemotherapy because of the possible risk for tumor recurrence. She is now doing well without any evidence of recurrence or metastasis 25 months after the surgery. Only 9 cases of GIST have been reported in children, and a review of those cases revealed GISTs in children would be associated with a better prognosis than in adults and that one third of pediatric GISTs presented with intestinal obstruction in the newborn period.

【背景】群馬県における神経芽細胞腫マススクリーニングは1984年7月より開始され今年で20年を迎えた.今回本県のマススクリーニングと発見症例の予後について検討したので報告する.【対象と方法】生後6カ月の乳児を対象として神経芽細胞腫マススクリーニングを施行した.検査は尿中のVMAおよびHVAを測定し行った.検査値が高値の症例は医療機関に紹介され神経芽細胞腫の精密検査を受けた.マススクリーニングにて発見された神経芽細胞腫症例は全例登録し, またこの間にマススクリーニング以外で診断された神経芽細胞腫についても予後の追跡を行った.【結果】2003年3月までに343,812例が受診し, 2,800例が精密検査を受診している.そのうち65例が神経芽細胞腫と診断された.この間に発生した神経芽腫総数は97例で, マススクリーニング発見例は67.0%を占める.マススクリーニング発見例に早期例の多いことが認められた.マススクリーニング陰性例が14例 (14.4%) に認められており, 死亡例の60%はこのマススクリーニング陰性で発症した症例であった.死亡例の他の40%はマススクリーニング受診以前またはマススクリーニング非受診で発症した症例であった.【結語】マススクリーニング開始後の神経芽細胞腫の発見例は増加したが進行神経芽細胞腫例の減少は認められなかった.神経芽細胞腫死亡例は近年減少しており, 治療技術の進歩と考えられた.厚生労働省の決定に基づき群馬県においても検査事業については平成16年4月から休止となることが決定された.

A transient myeloproliferative disorder (TMD) occurs in 10% of the infants with Down syndrome. While most cases resolve within a few months, in 20% of them TMDs are life-threatening or fatal. We encountered 4 patients with TMD, including 1 patient who died of liver failure and disseminated intravascular coagulation. Suspecting involvement of proinflammatory cytokines, we serially assayed them in patients’ sera. Cytokines were significantly more abundant in patients than in controls. Interleukins 1 and 2, tumor necrosis factor alpha, interferon gamma, and granulocyte-macrophage colony-stimulating factor were greatly increased, especially in the infant who died. Sustained cytokinemia is likely to participate in TMD pathophysiology, and very high serum concentrations might predict a poor outcome.

The effect of dipyridamole (DPM) on cell sensitivity to anticancer drugs was examined in acute lymphoblastic leukemia (ALL) cell lines. We established two ALL cell lines (KMO-90 and KMO-R) from bone marrow samples of a 12-year-old girl with ALL. The drug concentrations needed to reduce optical density to 50% of that of control cells (IC50) showed that KMO-R was about twofold more resistant to doxorubicin (DOX), mitoxantrone (MIT), vincristine (VCR), and etoposide (VP-16) than was KMO-90. Considering that both KMO-90 and KMO-R were established from a patient with ALL at the time of presentation and relapse, respectively, these two cell lines might be novel and useful models for research into the acquisition of drug resistance in ALL cells. Although cytotoxicity of DPM in KMO-90 was about 6% at 1 microgram/ml, DPM enhanced cell sensitivity to DOX, MIT, VCR, and VP-16 at this concentration. Cytotoxicity of DPM in KMO-R was less than 5% at 1, 5, and 10 micrograms/ml. In KMO-R, DPM enhanced cell sensitivity to these four drugs in a dose-dependent manner. The plasma concentrations achieved by oral administration of DPM is about 1 microgram/ml. At clinically achievable concentrations, DPM enhanced cell sensitivity to DOX, MIT, VCR, and VP-16 in both KMO-90 and KMO-R, thus showing DPM to be a useful agent for potentiating anticancer chemotherapy of hematopoietic malignancy.

Two cases of invasive aspergillosis are reported. Case 1, a 3-year-old boy with leukemic transformation of myelodysplastic syndrome, had an aspergillous infection in the hand, resulting in necrosis of the thumb. Case 2, an 18-year-old girl with acute megakaryoblastic leukemia, had an aspergillus skin infection on the wrist, accompanied by swelling and discoloration of the arm. In Case 2, angiography revealed a hypovascular lesion and vascular irregularity, suggesting that vessels were involved. Intraarterial infusion of urokinase and amphotericin B led to improvement of these symptoms in this patient. The combination of urokinase and an antifungal drug should be considered for intractable aspergillus infections involving the extremities.

Allogeneic bone marrow transplantation (BMT) with major ABO blood-group incompatibility is reported. The patient was a 12 year-old-boy with acute myelomonocytic leukemia who underwent allogeneic BMT from an HLA-matched sibling with major ABO blood-group incompatibility. Erythrocyte depletion of marrow cells using the COBE 2991 blood cell processor was carried out. Engraftment was successful with no sign of hemolysis, and confirmed on day 26 after transplantation. He is now being followed with no additional chemotherapy. A technique for rapid isolation of bone marrow mononuclear cells using Ficoll-Conray and the COBE 2991 blood cell processor is described.

Cytomegalovirus (CMV) infection, especially CMV pneumonia, is a serious event in immunocompromised individuals such as recipients of bone marrow transplantation. Since there is no effective treatment, prevention is the most effective way to control CMV infection. Blood transfusion is one potentially dangerous source of the virus. Screening for CMV negative donors is mandatory in order to provide blood components for these patients. We have screened 1, 827 donors for CMV antibody by using the gelatin particle agglutination test and ELISA. As it has been shown that the positivity rate is closely related to donor age, we tested mainly younger individuals. The results showed that the CMV antibody negative rate was 18.3%.

A case of infantile genetic agranulocytosis (Kostmann type) is reported. The mechanism of impaired granulopoiesis in this patient was also evaluated. The peripheral blood picture soon after birth was compatible with absolute neutropenia. Bone marrow aspiration showed no polymorphonuclear neutrophils beyond the promyelocytic stage. Stimulation with epinephrine or hydrocortisone produced no increase in granulocytes. He was isolated in a clean room, and placed on prophylactic administration of sulphamethoxazole and trimethoprim, thereby preventing serious infections. As it has been suggested that T-cells play an important role in the pathogenesis of Kostmann-type neutropenia, anti-lymphocyte globulin was tried. No increase in granulocytes was obtained, however. Administration of other drugs has so far produced no increases in granulocyte levels.

The Tokyo Children's Cancer Study Group (TCCSG) has performed prospective randomized controlled studies since 1984 for childhood acute lymphoblastic leukemia (ALL). Four hundred and ninety-eight newly diagnosed patients were treated with 5 different regimens designated as S1, S2 for a standard risk group (SRG), H1 and H2 for a high risk group (HRG) and HEX for an extremely high risk group of patients. We added intermediate-dose methotrexate as early intensification therapy in the S2 and H2 groups to reduce extramedullary and medullary relapses. Event-free survival of all patients at 4 years 6 months from the start of this regimen (median follow-up period 32 months) was 67.5%. The CNS relapse rate was significantly decreased to 2.2% compared to previously reported studies and our own experience. There were some unexpected complications of the CNS such as myelopathy and/or leukoencephalopathy. For the SRG early ID-MTX seemed to be useful to improve the prognosis, but triple intrathecal injections (TIT) should be limited in number. The 24Gy cranial irradiation (CRX) was effective but possibly excessive for the HRG. As evidenced by the success of the HEX group regimen, more intensive multi-drug consolidation in the early post-remission phase might be necessary to improve further the prognosis and to make it possible to shorten the treatment periods.

Blood samples taken from children with non-A, non-B hepatitis (NANBH) (n=11, Group 1) and from children with malignant disease and a history of frequent blood transfusions (n=39, Group 2) were tested for the presence of antibodies to C100-3 and the RNA sequences of hepatitis C virus (HCV). The antibody was studied in all cases. The RNA was studied by means of the polymerase chain reaction in all cases of Group 1 and 23 cases of Group 2. Both antibody and RNA were detected in two out of the eleven children in Group 1, both of whom had received blood transfusions several months prior to the test. Neither antibody nor RNA was detected in the remaining cases in Group 1.Antibody was positive in two out of the 39 Group 2 children, and RNA was positive in five out of 23. In Group 2, no cases were positive for both tests. An increase in blood GPT level was noted in all cases of Group 2 with positive results.In conclusion, HCV infection is relatively rare in children of NANBH. There is a considerable discrepancy between the presence of antibody to C100-3 and the presence of RNA sequences.

Histology after intensive induction chemotherapy is expected to become a beacon indicating when and how extensively radical surgery and lymph node dissection should be performed in advanced neuroblastoma. A thorough histologic review of surgical specimens was undertaken.All specimens from 34 patients who were pretreated intensively (or =3 cycles) with recent chemotherapy were reviewed. Thirty patients were12 months of age with stage 3/4 disease, and 4 were12 months of age but with MYCN-amplified stage 4 diseases. After 3 to 7 cycles (mean, 4.3 cycles) of induction chemotherapy, patients underwent radical surgery of the primary tumor and lymph nodes in all retroperitoneal sections. A single pathologist reviewed all of the specimens, and histologic chemotherapeutic effects were graded as: (+++),1% viable tumor; (++), 1%-10% viable tumor; (+), 11%-50% viable tumor; (+/-), 51%-90% viable tumor; and (-),91% viable tumor.Grade (+++) effects were observed in 56% of patients treated with the new regimens, whereas grade (+++) was seen in only 20% treated with regimens before 1991. Operation time and blood loss were 7 hr and 6 min (P = 0.087) and 646 ml (P = 0.064), respectively, in patients with5 cycles (mean, 5.3 cycles) of chemotherapy, while they were 7 hr and 50 min and 1,168 ml, respectively, in those with approximately 3 cycles (mean, 3.2 cycles). Histologically, metastases were found in the contralateral nodes beyond the aorta in 92% of those whose tumor originated on the left, and in 80% of those with tumors occurring on the right.Five cycles of induction chemotherapy did not improve histologic chemotherapeutic effects, but helped to facilitate a shorter operation time and less blood loss than 3 cycles of chemotherapy. Surgery after 5 cycles of (98)A(3) also appears to be easier to perform than that after 3 cycles of A(1)/new A(1). Only 14% of the children treated before 1985 with the St. Jude protocols experienced grade (+++) chemotherapeutic effects, and 22% of the patients treated before 1991 with regimen A(1), or new A(1) of the Study Group of Japan showed grade (+++) effects, whereas 56% of the patients treated after 1991 with either regimen A(3) or (98)A(3) exhibited grade (+++) chemotherapeutic effects. Histologic chemotherapeutic effects were roughly parallel with a good prognosis.

The prognosis for children with Wilms’ tumor is reported to be excellent in those who are less than 2 years of age at diagnosis and who have a stage I/favorable-histology tumor with specimen weight less than 550 g. We report on a patient with Wilms’ tumor who belonged to this group but who developed pulmonary metastases, and we discuss the diagnostic and therapeutic problems in such patients. The importance of careful evaluation of the renal sinus should be emphasized.

A newborn girl with neuroblastoma presented with hypertension (blood pressure 200/140 mm Hg). The concentration of active renin in the ipsilateral renal vein was exceedingly high compared with those in the other venous systems, and angiography results showed narrowing of the contralateral 2 renal arteries. The tumor regressed in size after chemotherapy, but the blood pressure remained high. Percutaneous transluminal angioplasty (PTA) for the left renal arteries was performed twice, the first one at 5 months of age, which achieved some success in the recovery of impaired kidney function. At 8 months of age, she underwent radical resection of the neuroblastoma and removal of the right kidney, and the blood pressure promptly returned to normal postoperatively. The current patient represents the second youngest, well-documented case of renovascular hypertension with neuroblastoma in early infancy.

Objective : The International Neuroblastoma Staging System (INSS) and Pathology Classification (INPC) were applied to analyze the results of treatment of 644 patients with neuroblastoma treated in Japan during the years from 1995 to 1999, and it was found that the pathology classification (INPC) showed the strongest relevance to prognosis compared to other factors such as stage,MYNC amplification, DNA ploidy and 1p-deletion. Current results of treatment for advanced neuroblastoma are still not satisfactory, so innovative therapeutic methods have been sought during the past 10 years.Methods : Prospects for irinotecan and recombinant human endostatin (rhEndostatin) were studied experimentally and clinically.Results. Irinotecan is a water-soluble derivative of camptothecin, which is isolated from a Chinese tree,Camptotheca acuminata; Its effectiveness against neuroblastoma was confirmed byin vivo preclinical studies, and phase I clinical trials in Japan concluded the maximum tolerated dose of this agent is 160–180 mg/m2/day for 3 consecutive days, repeated after 25 days off. Phase II trials with this dose began, and we could obtain some encouraging results with the clinical use of irinotecan. rhEndostatin has been studied inin vivo experimental models. The action of rhEndostatin was quite different from those of other cytotoxic chemotherapeutic agents, and continuous administration of this substance showed a more marked anti-effect than its intermittent use.Conclusion : Irinotecan appears to be promising when it is given to the patients neuroblastoma, whereas rhEndostatin needs to have more preclinical studies before it is used in patients.

Autologous red cells were collected from five normal bone marrow donors aged 7-14 years (median, 10 years). Recombinant human erythropoietin was administered to four of the five donors to enhance hematopoiesis. The median volume of blood removed from the donors was 18.2ml/kg. Preoperative blood donation and retransfusion led to no significant complications. No donors required homologous blood transfusion. This technique is useful for marrow donors even in the pediatric age group.

PURPOSE: We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy. PATIENTS AND METHODS: Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92–13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis. RESULTS: The mean (± SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% ± 3.4% and 81.5% ± 2.2%, respectively, at 5.5 years after diagnosis. EFS rates by risk category were similar (60.2% ± 6.0% for standard risk, 57.7% ± 5.6% for high risk, and 62.5% ± 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% ± 2.7%, 80.0% ± 4.1%, and 72.1% ± 4.5%, respectively, P < .0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% ± 7.9% (standard risk), 42.6% ± 8.1% (high risk), and 9.6% ± 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important. CONCLUSION: Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.

Serum alpha-fetoprotein (AFP) is elevated in 96.6% of infants and children with hepatoblastoma and hepatocarcinoma. Serum AFP was of normal level in only one case of immature-type hepatoblastoma, and very low in only one case of fetal-type hepatoblastoma among 43 cases reviewed in 1986. Recently, a case of hepatoblastoma with very low serum AFP was encountered in the authors' surgical department. In October 1998, a 55-month-old girl was admitted. Her birth weight was 717 g. A large space-occupying lesion (SOL) located in the left lobe of the liver was seen by magnetic resonance imaging (MRI), and her serum AFP level was 322 ng/mL with a subfractionation pattern of the "benign liver disease" type based on reactivity with lens culnaris hemagglutinin and concanavalin A. The patient underwent successful left lobectomy, and histological examination showed that the tumor, weighing 268 g, was hepatoblastoma of the well-differentiated, fetal type. Immunohistochemistry findings for AFP were negative. A hepatic mass in infants and children with low serum AFP level indicates the presence of either well-differentiated or immature hepatoblastoma, or fibrolamellar hepatocellular carcinoma. Subfractionation of AFP may contribute to the differential diagnosis of these subtypes.

A case of erythroleukemia (EL) associated with monosomy 7 is reported. The EL was diagnosed 20 months after the initial diagnosis of monosomy 7 was made. An immunologic study of the blast cells using a monoclonal antibody was positive for glycophorin A, which suggested that they were of erythroid origin; this was confirmed by electron microscopy. Chemotherapy was started with low dose cytarabine. However, the patient had severe bone marrow suppression and died of pneumonia. Our case shows that monosomy 7 is an abnormality of the pluripotential stem cells, including erythroid cells, that resulted in a true erythroid neoplasm.

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on cytokine profile was evaluated in a case of severe congenital neutropenia. The plasma levels of cytokines were measured before and during rhG-CSF therapy. These included G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha, interleukin-1 beta, interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4, interleukin-6 (IL-6), and tumor necrosis factor-alpha. Soluble interleukin-2 receptor (sIL-2R) was measured serially during rhG-CSF therapy. Lymphocyte subpopulations including CD2, CD3, CD4, CD8, CD19, CD20, and CD25 were also measured, rhG-CSF was administered once daily as a 30-min infusion. The patient was treated with increasing dose levels of 100, 200, 400, 800, and 1,600 micrograms/m2/day. The level of endogenous G-CSF was elevated to 334 pg/ml before treatment and GM-CSF, IL-2, IL-3, and IL-6 were slightly elevated. Clinically, he showed a moderate response to a high dose of rhG-CSF (1,600 micrograms/m2/day). Plasma levels of G-CSF markedly increased during therapy but plasma levels of other cytokines did not show significant changes during therapy and lymphocyte subpopulations did not significantly change. A drastic increase in sIL-2R expression was observed after rhG-CSF infusion and an increase in sIL-2R expression occurred even before a major increase in granulocyte counts. These results showed that a high dose rhG-CSF therapy may influence the cytokine network as judged by the increased sIL-2R expression.

A case of congenital leukemia with monosomy 7 is reported. Immunological study of the blast cells using monoclonal antibodies was suggestive of both myelomegakaryocytic and T-lymphoblastic leukemia. Chromosomal analysis of the bone marrow cells showed monosomy 7. Chemotherapy was initiated with a combination of adriamycin, cytosine arabinoside, 6-mercaptopurine, and prednisolone. The patient obtained complete remission, which has been maintained for 4 years and 1 month. He receives no chemotherapy now. Our case shows that monosomy 7 in congenital leukemia is rare, but the presence of monosomy 7 in congenital leukemia does not necessarily indicate a poor prognosis.

The clinical course of a 14-year-old boy who developed biopsy-proven minimal change nephrotic syndrome (MCNS) prior to institution of therapy for Hodgkin's disease (HD), mixed cellularity histologic subtype, is presented. In the first week of radiotherapy to the major site of disease in the neck, BUN and creatinine levels rose to 98 mg% and 8.4 mg%, respectively. During the second week of treatment, levels gradually decreased becoming normal in the third week. Body weight gradually decreased in the second week of radiotherapy, falling rapidly in the third and fourth week when diuresis was greatest. Although urine protein concentration fell initially, the concentration remained 1 + or more for 10 weeks following radiotherapy. Following radiotherapy to the neck, staging laparotomy demonstrated a single focus of Hodgkin's disease in the spleen. Radiotherapy was given to the splenic pedicle: six courses of multiagent chemotherapy (MOPP) followed. The boy remains free of any evidence of either HD or MCNS 33 + months from the time of the diagnosis. Circulating lymphocytes showed normal responses to stimulation by phytohemaglutinin, Concanavalin A, and pokeweed mitogens. The patient's monocyte-macrophage-mediated antibody-dependent cellular cytotoxicity (ADCC) was low both prior to and following radiotherapy. Lymphocyte-mediated ADCC was normal at both of these times.

A clinical analysis was made on twenty-four children with non-Hodgkin's lymphoma.The patients ranged in age from ten months to 14 years. The male-to-female ratio was 2 : 1. The annual incidence of the patients were increasing. Seven patients had mediastinal masses and five patients presented with abdominal involvement. Four patients had Stage I, two Stage II, eleven Stage III and seven Stage IV, according to Murphy's staging system.The long-term survival rate was only 20% before 1980. After 1980, ten patients had treatment with modified LSA2L2 protocol. The two year survival rate of these ten patients was 71.1%. Three patients are off therapy now.These data suggest a possible advantage for combined modality of treatment.

This is a case report of a cystic duplication of the cecum in a 6-month-old female infant, which was lined by both columnar and squamous epithelium. This squamous epithelium did not resemble esophageal epithelium but dermal epithelium. The so-called split notochord theory can explain the possibility of the coexistence of ectoderm and entoderm components. However, the present case had no vertebral abnormalities.